Grand Round 06/10/2009 Martin O. Weickert and colleagues Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism Neck & Hormones

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Grand Round 06/10/2009 Martin O. Weickert and colleagues Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism Neck & Hormones Slide 2 thyroid thyrotoxicosis (2% of UK population) hypothyroidism (9.3% (w), >60 yrs up to 16%; 1.35% (m)) parathyroid glands hyperparathyroidism (prim HPT < 0.1 3.4%, with age; sec HPT i.e. 80% in chronic haemodialysis patients ) hypoparathyroidism (most common post-surgery; otherwise rare) Endocrine active organs in the neck Yu et al. Clin Endocrinol 2009; Franklyn ESE abstracts 2009 Slide 3 An interesting case. Steph Horne House Officer Slide 4 Demographics 35 year old Caucasian Female self admission to A&E Slide 5 Presenting complaint upper abdominal pain epigastric area: burning/sharp in nature bloody diarrhoea vomited 15 times, diarrhoea for 5 days not able to tolerate any oral food/fluids similar episode 6 months ago OP endoscopy booked but DNA Slide 6 And the rest PMHX: appendix removed 6 years ago hyperthyroidism anxiety SHX: smoker 4-5 per day mild alcohol intake on methadone treatment Slide 7 On examination: Temperature:36.3 BP:174/112 PR:99 RR:24 O2 Sats:99% OA Mews:2 Pain score:3 (0-3) Chest clear HS I + II + 0 CNS intact Epigastric pain No Organomegaly BS + Unable to demonstrate guarding PR: Empty Rectum Slide 8 Impression.. perforated ulcer gallstones GORD pancreatitis gastroenteritis Slide 9 The blood results electrolytes: NAD WCC: 14.42, Hb: 11.8, Plts: 417 alk Phos: 227, ALT: 36, Amylase: 33 Slide 10 TIMELINE Surgical team referral Admitted to SAU OGD and Colonoscopy Discussions re; Laparotomy A&E: Abdo pain and diarrhoea Impression: Acute abdomen AXR/CXR: NAD Gastro referral Slide 11 Then along came. TSH < 0.02 mU/L (0.35 6 mU/L) free T3 36.3 pmol/L (2.8 7.1 pmol/L) free T4 > 100 pmol/L (9 26 pmol/L) Slide 12 Treatment symptomatic relief : beta blockers carbimazole USS thyroid gland thyroid autoantibodies Slide 13 The result diarrhoea resolved tremor/anxiety improved discharged with endocrine follow up Slide 14 Common causes of thyrotoxicosis Graves` disease toxic adenomas toxic multinodular goitre thyroiditis ingestion of excessive exogenous thyroid hormone iatrogenic, inadvertent, or surreptitious Slide 15 Some rarer causes TSH-secreting pituitary adenoma struma ovarii ectopic production in ovarian teratomas extremly high levels of hCG choriocarcinomas, germ cell tumours Slide 16 Classical symptoms of thyrotoxicosis hyperactivity, irritability, altered mood sleep disturbances sweating, heat intolerance palpitations weight loss, occasionally weight gain (polyphagia) oligo-/amenorrhoea, loss of libido Slide 17 unspecific in aged patients... tiredness, apathy, depression dementia, confusion, psychosis GI symptoms AF, worsening of angina pectoris, or congestive heart failure Slide 18 Thyrotoxic periodic paralysis (TPP) 2% in Asians, rare in Caucasians (0.15%) hyperthyroidism-related hypokalaemia sudden shift of K+ into cells associated with exercise inducible by carbohydrate + insulin challenge presentation in ED with acute muscle weakness systolic hypertension, tachycardia, high QRS voltage, first degree AV block McFadzean BMJ 1967, Lin Mayo Clin Proc 2005 Slide 19 Biochemical findings in thyrotoxicosis low TSH Slide 20 Other states with low TSH secondary hypothyroidism low normal or normal TSH low fT4 usually associated with deficiencies of other pituitary hormones thyroid sick syndrome ? aquired transient central hypothyroidism (Chopra JCEM 1997) low TSH (but not completely suppressed) low fT4 and fT3 Slide 21 Biochemical findings in thyrotoxicosis low or suppressed TSH increased fT4 and/or fT3 in overt thyrotoxicosis check for isolated fT3 thyrotoxicosis normal fT4 and/or fT3 in subclinical thyrotoxicosis increased risk of osteoporosis; evtl symptomatic frequently increased auto-Abs level in AIT Slide 22 Further changes... normocytic anaemia increased LFTs increased bone AP hypercalcaemia, hyperphosphataemia low albumin mild leukopenia low cholesterol Slide 23 24-hour variation of TSH HormoneCircadianSleep-wake homeostasis Cortisol ++++ Testosterone +++- GH ++++ PRL +++++ adapted from McDermott: Sleep and Endocrinology 2009 Slide 24 24-hour variation of TSH HormoneCircadianSleep-wake homeostasis Cortisol ++++ Testosterone +++- GH ++++ PRL +++++ TSH +++++ adapted from McDermott: Sleep and Endocrinology 2009; Patel Clin Sci 1972 Slide 25 Circadian rhythm of TSH ? less bioactive and differently glycosylated TSH molecules secreted during the night (Persani et al JCEM 1995) Russell et al. JCEM 2009 Slide 26 Circadian rhythm of TSH and fT3 circadian rhythm of fT3 delayed by 90 min clinical relevance? drug induced increase of TSH, e.g. metoclopramide (Scanlon JCEM 1980)) Russell et al. JCEM 2009 Slide 27 Interaction with SHBG oral contraceptives may not be fully protective in thyrotoxicosis SHBG (Ford Clin End 1992) clearance of contraceptives caution in fertile female patients after radioiodine therapy Slide 28 An orthopaedic outlier ! Noushad Slide 29 History 59 year old lady attended A&E at 01.42 am, 16/7/09 fell down in the toilet injury to left arm deformity of left arm No orthopaedic intervention needed! W20 Slide 30 History increasing confusion- 16 weeks weight loss and bilateral leg pains for the same period was not mobilising, just stayed in bed! no medical help sought until the fall fracture of right olecranon in 2006 after a trivial fall Slide 31 Further story left humerus was painful and deformed X-ray showed referred to ortho no ortho intervention needed, can go home with fracture clinic appointment Slide 32 Further story patients daughters mentioned the poor physical and mental state, refuses to take her home 04.45- patient c/o of right thigh pain X-ray ordered Slide 33 Blood investigations urea 9.0, creatinine 64, Na 143, K 4.0 adjusted Ca 3.68, ALP 606, Alb 41 Hb 11.0, WCC 17.36, Neuts 15.29 TSH 2.71 CRP Modern vs classical pHPT abrupt increase in annual incidence since the early 1970s 0.15 (1965 1974) to 1.12 (1975) per 1000 persons (Wermers Ann Int Med 1997) introduction of screening > 85% of modern pHPT patients are asymptomatic or have unspecific symptoms Slide 45 Modern vs classical pHPT kidney stones only in 15-20% of patients with modern pHPT reduced BMD far subtler abnormalities in bone often radiographics NAD routine skeletal x-rays are no longer recommended (Bilezikian et al. JCEM 2002) Slide 46 Biochemical findings in pHPT increased PTH increased (or normal) calcium low normal fasting serum phosphate other associated findings may include increased chloride, Cl/phosphate ratio 33, elevated urinary pH (> 6), increased alkaline phosphatase Slide 47 Band keratopathy calcium-phosphate precipitation in medial and limbic margins of cornea Slide 48 Parathyroid bone disease thin cortices contrasting maintenance of trabecular bone patient with pHPTcontrol Biopsy specimens from iliac crest Parisien et al. JCEM 1990 Slide 49 Osteitis fibrosa cystica striking and generalised increase in osteoclastic bone resorption osteoclastomas (brown tumours) with osteous expansion and lucency fibrovascular marrow replacement increased osteoblastic activity Slide 50 salt-and-pepper appearance of the calvarium trabecular bone resorption with loss of definition of cortices Slide 51 subperiostal bone resorption along the radial aspects of the middle phalanges distal clavicular resorption radiological disappearance of some bones Slide 52 pHPT and vitamin D deficiency modern pHPT: bone disease mainly in patients with severe vitamin D deficiency however co-existing pHPT and vitamin D deficiency is very common! (Mossgaard Clin End 2005, Eastell JCEM 2009) association with PTH, Ca, ALP, accelerated bone turnover, larger parathyroid glands/tumours, greater likelihood of abnormal bones (Tucci Eur J Endocrinol 2009) calcium levels can also be normal Slide 53 Grey et al. JCEM 2005 Slide 54 Cholecalciferol tablets 1.25 mg (50000 units) weekly for 4 weeks, thereafter 1 tablet per month for 12 month Slide 55 suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Grey et al. JCEM 2005 Slide 56 ? Mechanisms PTH-induced increase in 1-alpha hydroxylase 1,25(OH) 2 D (calcitriol) inhibition of PTH gene transcription, protein production and parathyroid gland proliferation (Beckermann Am J Med Sci 1999) no association between change in 1,25(OH) 2 D and PTH levels (Grey JCEM 2005) no decrease of PTH with active Vit D metabolites (Lind Acta Endocrinol 1989) no relation 25(OH)D with 1,25(OH) 2 D in cross- sectional studies (Silverberg Am J Med 1999, Rao JCEM 2000) Slide 57 Mechanisms ? non-1,25(OH) 2 D induced effects of 25(OH)D and other metabolites on PTH production ? stimulation of VitD receptor in parathyroid tissue by VitD deficiency ? intracrine action of parathyroid-derived 1,25(OH) 2 D to reduce PTH Slide 58 low magnesium levels blunt the stimulation of parathyroid glands induced by low Vit D levels often normal PTH levels even when 25-OH VitD below 20 ng/mL unknown effects of hypomagnesia in patients with pHPT Interactions with magnesium Sahota et al. Osteoporos Int 2006 Slide 59 Further secrets parathyroid PTH levels normally decrease with age association pHPT with metabolic syndrome increased body weight in patients with pHPT (Bolland JCEM 2005, Meta-analysis) increased leptin and decreased adiponectin (Delfini et al Metabolism 2007) consider co-existing disorders in patients with pHPT drugs (thiazides, lithium), malabsorption, renal failure, tumours Slide 60 Familiar hypocalciuric hypercalcaemia (FHH) 2% of all asymptomatic hypercalcaemia dominantly inherited usually heterozygous loss of function mutation in the CaSR PTH inappropriately normal or high, lifelong Ca ++ and Mg ++, both of variable degree enlarged glands and mild parathyroid hyperplasia can oc